POS0670 EVALUATION OF UPADACITINIB IN RHEUMATOID ARTHRITIS PATIENTS WITH INADEQUATE RESPONSE TO FIRST-GENERATION JANUS KINASE INHIBITORS
Authors: M. Kamiya, S. Mori, K. Yamazaki, D. Togawa
Journal: Annals of the Rheumatic Diseases (2022)

Background Janus kinase inhibitors (JAKi) are effective in the treatment of patients with difficult-to-treat rheumatoid arthritis (D2T RA), regardless of previous use of biological disease-modifying antirheumatic drugs (bDMARDs), and receive equal billing with biological therapies in the latest version of the EULAR recommendations for treatment of RA 1 . However, as with bDMARDs, cases of discontinuation due to intolerance or inadequate response have been observed in patients treated with the so-called first-generation JAKi, leading to the development of a new generation of JAKi that aims to maximize efficacy and improve safety by enhancing kinase selectivity. The results of randomized controlled trials and meta-analyses suggest that the efficacy and safety of Upadacitinib (UPA) treatment are favorable. Although there have been no head-to-head trials between JAKi, a matched-adjusted indirect comparative study has shown a difference in efficacy between JAKi 2 , suggesting that the new generation of JAKi may be effective in rheumatoid arthritis patients with intolerance or inadequate response to first-generation JAKi. It is already apparent that a clear need exists for a JAK-IR trial to give guidance in those difficult patients who are JAKi non-responders 3 . Objectives To evaluate real world efficacy of a second-generation JAK1-selective JAKi UPA in single-center cohort of RA patients who had discontinued first-generation JAKi. Methods Patients with RA who had discontinued tofacitinib and/or baricitinib due to inadequate response or intolerance, regardless of whether they had used bDMARDs or not, were eligible for the study if they had received UPA by October 2021 and had been followed up for at least 12 weeks. Endpoints were Kaplan-Meier survival rate with inadequate response or intolerance as reasons for discontinuation, various disease activity assessments (DAS28-ESR, SDAI, CDAI, etc.), and patient reported outcomes (visual analogue scales (VASs) such as pain and stiffness, HAQ-DI, FACIT-Fatigue Scale, etc.) at 12 weeks. In addition, the reasons for discontinuation were investigated. Results Fifty-one patients were included in the study, all of whom had D2T RA and had used at least one bDMARD as well as JAKi. The mean (median) age was 72.7 (77) years, disease duration 18.0 (17) years, number of bDMARDs used 3.34 (3), number of JAKi used 1.3(1), 5 patients with methotrexate, 6 patients with prednisolone, and DAS28-ESR 3.83 (3.9). At 12 weeks, the overall survival rate was 94% (94.6% in 37 cases used as 2nd JAKi and 92.9% in 14 cases used as 3rd JAKi). For reference, there was no significant difference from the 100% of the 15 cases used as the 1st JAKi (P=0.49). DAS28-ESR &lt;3.2 and &lt;2.6 were achieved in 60.8% and 29.4%, VASs for pain and stiffness decreased by a mean of 12.9 mm (9 mm) and 12.1 mm (7 mm), respectively, and FACIT-Fatigue scale improved by a mean of 3.0 (1). The reasons for discontinuation in the three patients were inadequate efficacy in two and leg cramps due to venous thromboembolism in one. Conclusion UPA is more selective for JAK1 than first generation JAKi, and is expected to reduce adverse reactions caused by inhibition of JAK family members other than JAK1. The present study suggests that UPA is effective and well tolerated, regardless of the number and type of first-generation JAKi used in the past, albeit for a short period of time. Limitations include the small number of cases and the short time frame for discussing adverse reactions. References [1]Smolen JS, Landewé BM, Bijlsma WJ et al., EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2019 update. Ann Rheum Dis 2020; 79 :685–699. [2]Christopher JE, Ruta S, Vishvas G et al. A Matching-Adjusted Indirect Comparison of Upadacitinib Versus Tofacitinib in Adults with Moderate-to-Severe Rheumatoid Arthritis. Rheumatol Ther 2021; 8:167–181. [3]Peter Nash, Clinical use of Jak 1 inhibitors for rheumatoid arthritis. Rheumatology , Volume 60, Issue Supplement_2, May 2021, Pages ii31–ii38 Disclosure of Interests None declared